PMID- 38306432 OWN - NLM STAT- MEDLINE DCOM- 20240205 LR - 20240206 IS - 2375-2548 (Electronic) IS - 2375-2548 (Linking) VI - 10 IP - 5 DP - 2024 Feb 2 TI - T-FINDER: A highly sensitive, pan-HLA platform for functional T cell receptor and ligand discovery. PG - eadk3060 LID - 10.1126/sciadv.adk3060 [doi] LID - eadk3060 AB - Effective, unbiased, high-throughput methods to functionally identify both class II and class I HLA-presented T cell epitopes and their cognate T cell receptors (TCRs) are essential for and prerequisite to diagnostic and therapeutic applications, yet remain underdeveloped. Here, we present T-FINDER [T cell Functional Identification and (Neo)-antigen Discovery of Epitopes and Receptors], a system to rapidly deconvolute CD4 and CD8 TCRs and targets physiologically processed and presented by an individual's unmanipulated, complete human leukocyte antigen (HLA) haplotype. Combining a highly sensitive TCR signaling reporter with an antigen processing system to overcome previously undescribed limitations to target expression, T-FINDER both robustly identifies unknown peptide:HLA ligands from antigen libraries and rapidly screens and functionally validates the specificity of large TCR libraries against known or predicted targets. To demonstrate its capabilities, we apply the platform to multiple TCR-based applications, including diffuse midline glioma, celiac disease, and rheumatoid arthritis, providing unique biological insights and showcasing T-FINDER's potency and versatility. FAU - Cetin, Miray AU - Cetin M AUID- ORCID: 0009-0001-7711-0211 AD - BioMed X GmbH, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. FAU - Pinamonti, Veronica AU - Pinamonti V AUID- ORCID: 0000-0001-5253-095X AD - BioMed X GmbH, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. AD - Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany. FAU - Schmid, Theresa AU - Schmid T AUID- ORCID: 0009-0007-4796-6776 AD - BioMed X GmbH, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. FAU - Boschert, Tamara AU - Boschert T AUID- ORCID: 0009-0007-8957-5319 AD - Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany. AD - DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. AD - Helmoltz Institute for Translational Oncology (HI-TRON), Heidelberg, Germany. FAU - Mellado Fuentes, Ana AU - Mellado Fuentes A AUID- ORCID: 0009-0000-9193-1430 AD - BioMed X GmbH, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. FAU - Kromer, Kristina AU - Kromer K AUID- ORCID: 0009-0005-5617-7635 AD - BioMed X GmbH, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. AD - Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany. FAU - Lerner, Taga AU - Lerner T AD - BioMed X GmbH, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. FAU - Zhang, Jing AU - Zhang J AD - BioMed X GmbH, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. FAU - Herzig, Yonatan AU - Herzig Y AD - BioMed X GmbH, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. FAU - Ehlert, Christopher AU - Ehlert C AD - Heidelberg Institute for Theoretical Studies (HITS gGmbH), 69118 Heidelberg, Germany. FAU - Hernandez-Hernandez, Miguel AU - Hernandez-Hernandez M AUID- ORCID: 0000-0001-8503-1954 AD - BioMed X GmbH, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. FAU - Samaras, Georgios AU - Samaras G AUID- ORCID: 0000-0002-1538-0048 AD - BioMed X GmbH, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. FAU - Torres, Claudia Maldonado AU - Torres CM AD - BioMed X GmbH, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. FAU - Fisch, Laura AU - Fisch L AUID- ORCID: 0000-0002-0529-3186 AD - BioMed X GmbH, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. AD - Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany. FAU - Dragan, Valeriia AU - Dragan V AUID- ORCID: 0009-0008-7173-8199 AD - BioMed X GmbH, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. AD - Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany. FAU - Kouwenhoven, Arlette AU - Kouwenhoven A AD - Janssen Research and Development, Beerse, Belgium. FAU - Van Schoubroeck, Bertrand AU - Van Schoubroeck B AUID- ORCID: 0009-0000-1798-6927 AD - Janssen Research and Development, Beerse, Belgium. FAU - Wils, Hans AU - Wils H AD - Janssen Research and Development, Beerse, Belgium. FAU - Van Hove, Carl AU - Van Hove C AUID- ORCID: 0009-0002-9271-5689 AD - Janssen Research and Development, Beerse, Belgium. FAU - Platten, Michael AU - Platten M AUID- ORCID: 0000-0002-4746-887X AD - DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. AD - Helmoltz Institute for Translational Oncology (HI-TRON), Heidelberg, Germany. AD - Department of Neurology, Medical Faculty Mannheim, MCTN Heidelberg University, Mannheim, Germany. FAU - Green, Edward W AU - Green EW AUID- ORCID: 0000-0003-1922-2298 AD - DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. AD - Department of Neurology, Medical Faculty Mannheim, MCTN Heidelberg University, Mannheim, Germany. FAU - Stevenaert, Frederik AU - Stevenaert F AD - Janssen Research and Development, Beerse, Belgium. FAU - Felix, Nathan J AU - Felix NJ AD - Janssen Research and Development, Spring House, PA, USA. FAU - Lindner, John M AU - Lindner JM AUID- ORCID: 0000-0002-4940-5354 AD - BioMed X GmbH, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. LA - eng PT - Journal Article DEP - 20240202 PL - United States TA - Sci Adv JT - Science advances JID - 101653440 RN - 0 (Ligands) RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Receptors, Antigen, T-Cell) RN - 0 (HLA Antigens) RN - 0 (Histocompatibility Antigens Class II) SB - IM CIN - doi: 10.1126/sciadv.adi9091 MH - Humans MH - Ligands MH - *Histocompatibility Antigens Class I MH - *Receptors, Antigen, T-Cell/metabolism MH - HLA Antigens MH - Histocompatibility Antigens Class II PMC - PMC10836725 EDAT- 2024/02/02 18:42 MHDA- 2024/02/05 06:42 PMCR- 2024/02/02 CRDT- 2024/02/02 14:05 PHST- 2024/02/05 06:42 [medline] PHST- 2024/02/02 18:42 [pubmed] PHST- 2024/02/02 14:05 [entrez] PHST- 2024/02/02 00:00 [pmc-release] AID - adk3060 [pii] AID - 10.1126/sciadv.adk3060 [doi] PST - ppublish SO - Sci Adv. 2024 Feb 2;10(5):eadk3060. doi: 10.1126/sciadv.adk3060. Epub 2024 Feb 2.